The majority of persons infected with HIV in the US are over 50 years of age, and despite antiretroviral therapies (ART), often develop HIV-associated non-AIDS (HANA) conditions that are strikingly similar to chron- ic inflammatory diseases of aging, but that occur earlier than in uninfected individuals. Regulating inflammation (e.g. via macrophages) and removing the stimulus of inflammation (e.g. virus reservoirs, defective virus particles) in those under long-term HIV+ART as well as those recently-infected with HIV+ ART may be crucial to reversing accelerated aging and treating HANA conditions. The hypothesis of this R01 proposal is that tar- geting dysfunctional macrophages via liposome-bisphosphonate treatment will induce apoptosis and their re- placement with new cells that will better regulate and ameliorate inflammation as well as possibly reduce one of the virus reservoirs. The rationale is based on our earlier work using rhesus macaques whereby virus infec- tion of lung tissue macrophages, increased blood monocyte turnover rate, and higher levels of circulating in- flammatory cytokines dictated the tempo of disease progression in SIV-infected rhesus macaques. SIV levels increased in macrophages, but remained level in CD4+ T cells of the lung during later stages of infection. While shorter-lived interstitial macrophages (IM) of the lung became infected early after SIV infection and ex- hibited higher turnover, longer-lived alveolar macrophages (AM) maintained a lower turnover rate yet became infected only after blood monocyte turnover increased. ART reduced SIV infection in shorter-lived IM but failed to reduce virus levels after longer-lived AM became infected. We thus propose to target macrophages using bisphosphonates as an intervention strategy to reduce accelerated aging and HANA conditions.
The aims are:
Specific Aim 1. Determine if liposome-bisphosphonate treatment of SIV-infected rhesus macaques having undergone long-term ART will reduce and ameliorate inflamm-aging and HANA conditions. Rhesus macaques of 15-18 years of age (equivalent to humans at 50-65 years of age) will be infected with SIVmac239 and administered ART. After inflamm-aging / HANA biomarkers are expressed, half the animals will be treated with liposome-bisphosphonates that we hypothesize will produce apoptosis of macrophages and induce their replacement with recruited cells to reduce inflammation and ameliorate HANA conditions.
Specific Aim 2. Determine if liposome-bisphosphonate treatment of mid-older-aged rhesus ma- caques that were recently infected with SIV and administered ART can prevent or delay onset of in- flamm-aging and HANA conditions. Here we plan to infect 15-18-year-old rhesus macaques with SIV and initiate ART. After ART reduces virus levels, liposome-bisphosphonate treatment will begin. We hypothesize that earlier treatment with bisphosphonate will induce macrophage apoptosis and their replacement with fresh- ly recruited cells to prevent or delay onset of inflamm-aging and HANA conditions.
The proposed research is relevant to public health for testing an intervention strategy to alleviate chronic inflammation and disease associated with accelerated aging during HIV infection and antiretroviral therapy. This study utilizes a nonhuman primate model of SIV infection, antiretroviral therapies, and aging to determine if targeting macrophages with bisphosphonates will provide proof of principle for efficacy. The results are anticipated to move work forward to reverse or delay progression of inflammatory diseases associated with HIV infection, antiretroviral therapies, and accelerated aging in humans.
| He, Ziyuan; Allers, Carolina; Sugimoto, Chie et al. (2018) Rapid Turnover and High Production Rate of Myeloid Cells in Adult Rhesus Macaques with Compensations during Aging. J Immunol 200:4059-4067 |
